Episode #30: The Future of Lung Disease Interception with Dr. Ravi Kalhan

Dr. Albert Rizzo:
Welcome back to Lungcast, the monthly respiratory health podcast series from the American Lung Association and medical news site HCP Live. I'm your host, Dr. Albert Rizzo, Chief Medical Officer of the American Lung Association.

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We're ramping up to some interesting topics and maybe even some shows on the road in 2023, so stay tuned for all we have coming up. Today, I'm with our colleague Dr. Ravi Kalhan, Deputy Division Chief of Pulmonary and Critical Care Medicine at Northwestern University.

We're going to get into some core-level discussion on the modeling of respiratory health and pulmonary mechanisms, as well as the bolstered role of screening in lung cancer. We will also discuss the start of a major new study designed to further inform us on the state of respiratory health and the development of respiratory diseases.

Dr. Kalhan, thank you for speaking with me today, and thank you for your work with the American Lung Association. I know you are one of the key principal investigators in this important American Lung Association cohort study. I would certainly like to circle back to that a bit later. First, I wanted to give you the opportunity to talk about the concept of respiratory health.

You and several of your colleagues published a perspective in the American Journal of Respiratory and Critical Care Medicine several years ago, I believe in 2018. In that article, you offered a conceptual model of respiratory health. You pointed out that respiratory health is often defined as the absence of respiratory disease, with no intermediate state of impaired respiratory health, and then compared that to the definition analogous to one in cardiac health and disease. Can you please explain to our listeners the model you are proposing?

Dr. Ravi Kalhan:
Yeah, well thanks for having me, Al. It's really great to chat with you about this.

This concept of impaired respiratory health is predicated on the notion that you and I, and every other lung doctor from time immemorial, have defined disease by physiologic impairment. So, we have always used pulmonary function testing as our key definition of COPD, for example, whereby if someone crosses a threshold of abnormal lung function—in that case, the forced expiratory volume in one second to the vital capacity ratio being less than 70 percent—then you have obstructive lung physiology, and you have COPD.

But that might happen later. Take, for example, someone who crosses that threshold at age 57. We then behave as if that person had been “normal” at 50, 45, or 40, and did not have lung function below that threshold. But of course, they were not normal. They didn't wake up one morning and develop chronic lung disease—it went through a progression across their life course.

By ignoring what we term the intermediate phenotypes—what someone looks like as they transition from ideal respiratory health, as good as they get in their early 20s, to chronic lung disease—we eliminate the opportunity to intercept the process and actually change the public health trajectory.

On an individual level, it's really important to define disease. On a public health level, it's important to think about these intermediate impairments so we can actually try to intercept them. Cardiovascular people have more information than we do. When they say in primary care, “We should check cholesterol,” it's because an elevated LDL cholesterol is an intermediate phenotype of impaired cardiovascular health that is on the pathway toward atherosclerosis and heart attacks.

Studies like the Framingham Heart Study, started in the 1940s, with a longer time period than we have, helped define this. That conception of intermediate phenotypes—high cholesterol, high blood pressure, physical inactivity—inform disease interception and health promotion, reducing the burden of heart attacks in society.

We need to think creatively in the respiratory space about how to do the same thing. That’s the fundamental thought behind the framework presented in that paper.

Dr. Albert Rizzo:
Well explained. In that paper, you go on to point out two concepts that help explain this model: pulmonary reserve, as reflected by peak lung function, and susceptibility, as reflected by risks for future accelerated decline in lung health. Can you explain the pulmonary reserve first?

Dr. Ravi Kalhan:
Yeah, so when we say pulmonary reserve, what we really mean is peak respiratory health. It's the amount of capacity and resilience someone develops through early life. Some kids are born premature, and we know they are at risk for lower peak lung function in young adulthood—they have less reserve.

We know that children born in houses with lots of secondhand smoke or other airborne pollutants, gases, vapors, or fumes are probably susceptible and acquire less peak respiratory health. RSV in childhood may also lead to lasting impairment, lowering peak lung development in young adulthood.

If your starting point in young adulthood is lower than someone with ideal growth, then you're at a disadvantage. Even if these people don’t smoke, work in a factory, or have other exposures, they may still be at higher risk for chronic lung disease. The question becomes: what can we do to enhance their resilience so they don’t experience chronic lung disease in the future?

Dr. Albert Rizzo:
So that goes on to the susceptibility part of the model. Once peak lung function has been reached, then some people are more susceptible to decline based on exposures or other risk factors. Is that correct?

Dr. Ravi Kalhan:
That's correct. Some people are resilient, some are not. We don’t fully understand why someone who smokes heavily may or may not develop COPD, emphysema, or lung cancer. If you have low reserve and are susceptible, that’s the highest risk group in our framework.

Dr. Albert Rizzo:
You touched on this a little earlier. In the absence of a specific biomarker for respiratory health, we are at a disadvantage. You mentioned cholesterol in cardiac disease and surrogate markers in cardiovascular cohort studies. Can you comment on similar markers for lung decline?

Dr. Ravi Kalhan:
Yes, studies like CARDIA, which I’ve worked on, allowed us to measure lung function in a cardiovascular cohort. CARDIA started in 1985 in the U.S. among 18- to 30-year-olds, around the time of peak respiratory health. Spirometry and cardiac CT scans were performed, and we could look at lung function decline and risk of emphysema or COPD.

There are biomarkers associated with future lung disease—measures of systemic inflammation like CRP or endothelial dysfunction like ICAM1. They reflect vulnerability but may not be causal. Cholesterol is helpful because it predicts heart attacks and is on the causal pathway to atherosclerosis, with pharmacotherapies available. For lung disease, we need targets we can intervene on, not just markers of risk.

Dr. Albert Rizzo:
The next topic is CT imaging as a potential biomarker for lung susceptibility. Many low-dose CT scans for lung cancer screening detect emphysema in asymptomatic individuals. Could this be used to alert clinicians to interventions such as smoking cessation?

Dr. Ravi Kalhan:
Yes, CT imaging is part of the answer. Detecting early lung injury allows intervention, primarily smoking cessation, and performing pulmonary function tests to guide treatment. Early pulmonary fibrosis can also be detected, allowing timely therapy.

More novel approaches, using machine learning on CT scans, may detect early forms of lung injury even before emphysema, fibrosis, or nodules appear. Longitudinal studies, like CARDIA with scans 10 years apart, help us understand if early lung injury predicts future problems and quantify risk.

Dr. Albert Rizzo:
Very good. The last topic is the American Lung Association’s Lung Health Cohort Study, funded by NHLBI and run through the ALA’s Airways Clinical Research Centers. Can you explain what the study is monitoring and how long-term results might define respiratory health?

Dr. Ravi Kalhan:
The Lung Health Cohort (ALA-LHC) is a community-based study enrolling adults aged 25–35 without chronic lung disease. We chose this age to capture peak respiratory health. Some participants may have lower reserve or higher susceptibility.

The study includes spirometry, lung CT scans, nasal lining fluid, blood sampling, and assessment of exposures such as smoking, vaping, physical activity, and geocoded environmental exposures. Baseline assessments will help us understand determinants of peak respiratory health and whether low pulmonary reserve in young adulthood translates to lung abnormalities or distinct biomarker profiles.

Our long-term goal is to follow participants throughout life, similar to the Framingham study for cardiovascular disease, to identify targets for intercepting chronic lung disease before it is clinically apparent—essentially finding the “cholesterol for the lung.”

Dr. Albert Rizzo:
I know there are several ancillary studies attached to this cohort. Can you comment on some of them and their role in advancing the science?

Dr. Ravi Kalhan:
One compelling sub-study relates to COVID-19. We aim to understand how COVID-19 infection impacts respiratory health in young adults. Many did not require hospitalization but experienced illness. We’re examining symptoms, biomarker profiles, and antibody responses to infection versus vaccination.

This approach also allows us to study respiratory viral infections more broadly, identifying those highly burdened by infections and assessing risk for future illness. Long COVID symptoms, including fatigue and brain fog, may also be assessed in this population. Careful, systematic measurement of respiratory symptoms will allow us to capture their long-term impacts.

Dr. Albert Rizzo:
Thank you for your time today, Dr. Kalhan, and best of luck with your important work in respiratory research. For our listeners who want more information, visit lung.org. Previous episodes have covered chronic lung disease, including our asthma episode with Dr. Mario Castro and COPD discussion with Dr. Melvin Hahn.

Be sure to subscribe and rate Lungcast on your preferred listening or watching platform, and visit lung.org and hcplive.com for more news and resources. Until next time, I’m Dr. Albert Rizzo. Remember, if you can’t breathe, nothing else matters.